キジにおけるモチリン、グレリンの同定とそれらの消化管運動調節における役割の解明

酪農学園大

Genetic liability for diet-derived circulating antioxidants, oxidative stress, and risk of osteoarthritis: a Mendelian randomization study

BackgroundAlthough well-documented, the causal relationships between diet-derived circulating antioxidants, oxidative stress, and osteoarthritis (OA) are equivocal. The objective of this study is to employ two-sample Mendelian randomization (MR) to investigate possible causal relationships among dietary-derived circulating antioxidants, oxidative stress damage indicators, and OA risk.MethodsSingle-nucleotide polymorphisms for diet-derived circulating antioxidants (ascorbate, β-carotene, lycopene, retinol, and α-and γ-tocopherol), assessed as absolute levels and metabolites, as well as oxidative stress injury biomarkers (GSH, GPX, CAT, SOD, albumin, and total bilirubin), were retrieved from the published data and were used as genetic instrumental variables. Summary statistics for gene–OA associations were obtained from publicly available and two relatively large-scale GWAS meta-analyses to date. The inverse-variance weighting method was utilized as the primary MR analysis. Moreover, multivariable MR was used to determine if mediators (BMI and smoking) causally mediated any connection. Furthermore, for each exposure, MR analyses were conducted per outcome database and then meta-analyzed.ResultsGenetically predicted absolute retinol level was causally associated with hip OA risk [odds ratios (ORs) = 0.40, 95% confidence interval (CI) = 0.24–0.68, FDR-corrected p = 0.042]. Moreover, genetically predicted albumin level was causally associated with total OA risk (OR = 0.80, 95% CI = 0.75–0.86, FDR-corrected p = 2.20E-11), as well as the risk of hip OA (OR = 0.75, 95% CI = 0.68–0.84, FDR-corrected p = 1.38E-06) and knee OA (OR = 0.82, 95% CI = 0.76–0.89, FDR-corrected p = 4.49E-06). In addition, MVMR confirmed that the effect of albumin on hip OA is independent of smoking initiation, alcoholic drinks per week, and moderate-to-vigorous physical activity levels but may be influenced by BMI.ConclusionEvidence from our study supports a potentially protective effect of high levels of retinol and albumin on OA risk

Molybdenum-Based Catalytic Materials for Li–S Batteries: Strategies, Mechanisms, and Prospects

Lithium–sulfur (Li–S) batteries are regarded as promising candidates for high-energy storage devices because of their high theoretical energy density (2600 Wh kg−1). However, their practical applications are still hindered by a multitude of key challenges, especially the shuttle effect of soluble lithium polysulfides (LiPSs) and the sluggish sulfur redox kinetics. To address these challenges, varieties of catalytic materials have been exploited to prevent the shuttle effect and accelerate the LiPSs conversion. Recently, molybdenum-based (Mo-based) catalytic materials are widely used as sulfur host materials, modified separators, and interlayers for Li–S batteries. They include the Mo sulfides, diselenides, carbides, nitrides, oxides, phosphides, borides, and metal/single atoms/clusters. Here, recent advances in these Mo-based catalytic materials are comprehensively summarized, and the current challenges and prospects for designing highly efficient Mo-based catalytic materials are highlighted, with the aim to provide a fundamental understanding of the sulfur reaction mechanism, and to guide the rational design of cathode catalysts for high-energy and long-life Li–S batteries

セキツイ ドウブツ ノ グレリン ブンプ ジュヨウタイ ホウシュツ チョウセツ キコウ オヨビ ショウカカン ウンドウ ニ アタエル エイキョウ

Ghrelin is a 28 amino acids peptide hormone produced in the gastric mucosal X/A-like cells. This peptide has a characteristic structure in which serine at position 3 is modified by fatty acid, such as n-octanoyl acid. Ghrelin acts on a G-protein coupled ghrelin receptor, previously called growth hormone secretagogue receptor (GHS-R) and regulates endocrine and exocrine functions, food intake, drinking water, glucose metabolism, energy homeostasis, cardiovascular function and gastrointestinal (GI) function (motility, secretion and mucosa proliferation). The multifunction of ghrelin is due to widespread distribution of ghrelin receptor in the central nervous system and peripheral organs. Ghrelin has been found mainly in the gastric mucosa and its sequence has been identified in the various vertebrates from fish to mammals. In vertebrate ghrelin, N-terminal sequence (1-7) including the fatty acid modification of 3rd serine is well conserved and this sequence is essential for its biological activity. Therefore, ghrelin is thought to be a multifunctional peptide conserved in the evolution process of vertebrates. In this review although ghrelin is a multifunctional peptide, its GI motility stimulating action has been focused because structures of ghrelin and its receptor are similar with those of motilin and motilin receptor, which are involved in the regulation of migrating motor complex (MMC) in the humans, dogs and house musk shrews (suncus). We summarized the effects of ghrelin on GI motility from fish to mammals (in vivo and in vitro studies) to determine universal function of ghrelin for regulation of GI motility. In mammals, ghrelin shows the GI motility stimulating actions through activation of ghrelin receptor on enteric neurons and primary afferent neurons of vagus nerve in rodentia (mice, rats and guinea-pigs). Enhancement of MMC by ghrelin and decrease of MMC by ghrelin receptor antagonist suggest that ghrelin mediates the phase III of the gastric MMC in mice and rats. However, ghrelin inhibits the gastric MMC in dogs by reduction of motilin release, suggesting that ghrelin depresses the motilin function in dogs. Suncus is a unique experimental animal in which both ghrelin and motilin cause gastric contractions, and ghrelin enhances the motilin action and motilin enhances the ghrelin action. Ghrelin cooperates with motilin for regulation of the gastric MMC in the case of suncus. In humans, ghrelin causes phase III-like contraction of MMC in the stomach at high dose but plasma ghrelin concentration is low and stable during MMC, indicating that ghrelin does not regulate the MMC in the human. In non-mammals, although motilin causes the contraction of bird, amphibian and fish GI tract, there are conspicuous species-related difference in the ghrelininduced actions on GI motility, i.e., ghrelin is effective causing contraction of crop and stomach in the chicken, but it is ineffective in the GI tract of quail and pheasant. In amphibians, ghrelin causes contraction of GI tract in the Xenopus but not in the bullfrogs, black spotted pond frogs and Japanese fire belly newts. In fish, ghrelin contracts zebrafish intestine but fails to cause contraction of goldfish and rainbow trout GI tract. Therefore, the physiological roles of ghrelin in the regulation of GI motility is not clear at present except for rodentia (mice and rats) and suncus. Further comparative biological studies for ghrelin using wide animal species might be necessary in future

Staphylococcus aureus increases Prostaglandin E2 secretion in cow neutrophils by activating TLR2, TLR4, and NLRP3 inflammasome signaling pathways

IntroductionIn clinical settings, dairy cows are often attacked by pathogenic bacteria after delivery, especially Staphylococcus aureus (S. aureus). Neutrophils have long been regarded as essential for host defense against S. aureus. Prostaglandin E2 (PGE2) can additionally be used as an inflammatory mediator in pathological conditions to promote the repair of inflammatory injuries. However, whether S. aureus can promote the accumulation of PGE2 after the infection of neutrophils in cows and its mechanism remain unclear. Lipoprotein is an important immune bioactive ingredient of S. aureus.MethodsIn this study, the changes in neutrophils were monitored in dairy cows infected with wild-type S. aureus (SA113) and an S. aureus lipoprotein-deficient strain (Δlgt); meanwhile, we established whether pattern recognition receptors mediate this process and whether S. aureus lipoproteins are necessary for causing the release of PGE2 from cow neutrophils.ResultsThe results showed that Δlgt was less effective than SA113 in inducing the production of IL-1β, IL-6, IL-8, IL-10, and PGE2 within neutrophils; furthermore, TLR2, TLR4, and NLRP3 receptors were found to mediate the inducible effect of lipoprotein on the above inflammation mediators and cytokines, which depended on MAPK and Caspase-1 signaling pathways. In addition, TLR2, TLR4, and NLRP3 inhibitors significantly inhibited PGE2 and cytokine secretion, and PGE2 was involved in the interaction of S. aureus and neutrophils in dairy cows, which could be regulated by TLR2, TLR4, and NLRP3 receptors. We also found that S. aureus was more likely to be killed by neutrophils when it lacked lipoprotein and TLR2, TLR4, and NLRP3 were involved, but PGE2 seemed to have no effect.DiscussionTaken together, these results suggest that lipoprotein is a crucial component of S. aureus in inducing cytokine secretion by neutrophils as well as killing within neutrophils, which could be accomplished by the accumulation of PGE2 by activating MAPK and the Caspase-1 signaling pathways through TLR2, TLR4, and NLRP3 receptors. These results will contribute to a better understanding of the interaction between S. aureus and host immune cells in dairy cows

セキツイ ドウブツ ニオケル モチリン ノ ヒカク セイブツガク : コウゾウ ブンプ ジュヨウタイ オヨビ ショウカカン ウンドウ コウシン サヨウ

Almost 50 years have passed since the discovery of motilin. However, actions of motilin on gastrointestinal (GI) motility are different from species and motilin does not cause GI contraction in rodents (rats, mice and guineapigs). Additionally, actions of motilin also differ from GI regions and experiment conditions (in vitro or in vivo) even in the same species. Due to these characteristics of motilin responses, number of papers for motilin research is small compared to that of a motilin-related peptide, ghrelin (discovered at 1999) and knowledge of motilin and its receptor have been limited and unsorted. Recently motilin and its receptor (MLN-R) have been also identified in non-mammalian vertebrates (birds, reptiles, amphibians and fish). This review summarized the distribution, structure, receptor expression and GI motility-stimulating action of motilin in a range of species including fish to mammals. A highly conserved N-terminal structure (1-10) commencing the amino acid indicated by phenylalanine was thought to be essential for GI motility stimulating action of motilin in mammalian/avian motilin lineage. Reptile motilin is considered to be in the transition stage to mammalian/avian type, i.e. alligator motilin has phenylalanine but other motilins (snake, turtle and lizard) have tyrosine at first position of N-terminal. On the other hand, the sequences of fish and amphibian motilins are quite different from those of mammalian/avian motilin. Therefore, in the molecular evolution of motilin, there may have been a major event at the time the reptiles emerged. The differences in motilin sequences are due to mutations in protein coding domains during species evolution which were probably motivated by adaptation. In contrast, the C-terminal sequence (11-22) is more conserved than that of the N-terminal, suggesting that the C-terminal may exert an as yet unknown function in addition to stimulation of GI motility as mediated via the N-terminal. Molecular biologically, MLN-R can be divided into two main groups: mammal/bird/reptile/amphibian clade (group A) and fish clade (group B). Group A can be divided into two clades: terrestrial type (mammals, birds and reptiles) and semi-aquatic type (amphibians). The clade of the terrestrial MLN-Rs can be further divided into three clades (mammals, birds/reptiles and reptiles (reptile-1)), and birds/reptiles clade is divided into birds and reptile-2 (alligator/crocodile MLN-Rs). Reptile-2 clade is included in the same umbrella with the bird clade, as in the case of motilin structure. Group B may have characteristics that match the aquatic inhabiting nature of fish. In mammals, motilin is an important regulator of the phase III of interdigestive migrating motor complex (MMC) in the stomach of humans, dogs, house musk shrews, monkeys and opossum through activation of smooth muscle cells, enteric neurons or vago-vagal reflex pathway. Gastric MMCs induced by motilin contribute to maintenance of normal GI functions and transmits a hunger signal from peripheral (stomach) to brain. Motilin has been identified in other mammals (rabbits, ruminants and pigs), but roles of motilin in these animals have not been understood well due to different physiological characteristics of MMC and different feeding behavior. In birds, motilin and MLN-Rs have been also identified and motilin caused contraction of small intestine and contributed to initiation of rhythmic oscillating complexes in the intestine. Motilin did not cause the contraction of GI strips in the fish but caused the contraction of urodelian amphibians (newts) and reptiles in a GI region-dependent manner as in the bird/mammals. Through these comparative studies in different vertebrates, it can be seen for the first time that the GI motility-stimulating action of motilin is not common in vertebrates because motilin stimulates GI contraction in mammals, birds, reptiles and amphibians but not in fish. This review, covering a wide range of motilin research including not only mammals but also non-mammals (comparative biology of motilin), will help to understand the contribution of the motilin system to animals, including evolution